Hippocampal neurons from the fetal trisomy 16 mouse (Ts16), a model for Down syndrome, showed increased high-voltage- activated calcium currents in comparison to control diploid neurons. Ts16 neurons also bound more L-type calcium ligand. NMDA evoked currents in Ts16 neurons did not differ from currents in normal diploid neurons. Thus, this trisomy condition affects ionic responses that could have an impact on mental retardation in Down syndrome. We also investigated long-term potentiation (LTP), a model for learning and memory, in a new genetic model of Down syndrome, trisomy 16Dn mice, trisomic only for the part of mouse chromosome 16 that corresponds to human chromosome 21. The mice survive into adulthood. In hippocampal slices from trisomy 65Dn mice, LTP, induced by a single tetanizing pulse train at 100 Hz, was reduced, consistent with their learning impairment.